: The proposed project was designed to analyze sex differences in the antinociceptive effects of mu opioids with varying degrees of relative efficacy. Previous reports employing thermal nociceptive stimuli suggest that the relative efficacy of mu opioids is lower in female than male rats. Experiment I will investigate this pharmacologically by administering various doses of the irreversible mu antagonist beta-funaltrexamine (beta-FNA) in combination with a range of mu opioid agonists. The degree of rightward and downward shifts in the agonist dose effect curve can be used to obtain estimates of an agonist?s efficacy ("e") for each sex, as well as the fraction of receptors still available for agonist interaction after blockade with an irreversible antagonist ("q"). Although previous studies have generally employed assays of thermal nociception to examine sex differences, there are data suggesting that sex differences may depend on the particular nociceptive assay. Thus, Experiment II will examine the antinociceptive effects of mu opioids using a mechanical nociceptive stimulus. Finally, Experiment III will identify the neuroanatomical sites of action that determine sex differences in mu opioid-induced antinociception. Using a thermal nociceptive stimulus, the potency and effectiveness of spinally administered mu opioids will be examined in males and females. Additionally, peripheral opioid receptor activity will be assessed with the use of a chemical nociceptive stimulus. The present proposal will provide a quantitative estimate of sex differences in the efficacy of mu opioids, examine the specificity of sex differences in opioid-induced antinociception across nociceptive stimuli that are subserved by different neural circuitry, and identify the neuroanatomical sites that determine sex differences in opioid-induced antinociception.